1. Field of Invention
The present invention relates to a compound and a pharmaceutical composition containing the compound and its medical use, and more particularly to pyrazolo-pyrimidones derivatives, their pharmaceutical compositions and application in opener of KCNQ potassium channel.
2. Description of Related Arts
KCNQ potassium channel is an important branch in family of potassium channel. At present, there are many different types of KCNQ potassium channels expressed in many different types of cells. According to their structural characteristics, 5 major types are categorized, which are KCNQ1, KCNQ2, KCNQ3, KCNQ4 and KCNQ5. Wherein KCNQ1 (also known as KVLQT) is mainly located in the heart and KCNQ2-5 are mainly located in the central and peripheral nervous systems, inner ear (KCNQ4), and muscle tissue (KCNQ5). Research studies have shown that both KCNQ1 and KCNE1 are coding for cardiac delayed rectifier potassium channel (IKs), and mutation of the channel can lead to hereditary long QT syndrome (LQT1, Sanguinetti M C, Ann N Y Acad. Sci. 1999; 868:406-13); KCNQ4 is gene coding for outer hair cell of ear and member of type-1 hair cell of vestibular organ which is associated with potassium channel, the mutation of which can lead to hereditary deafness; KCNQ2 and KCNQ3 channel genes co-express and generate current which is the molecular basis of neuronal M-type potassium current. M channel plays an important role in regulating the excitability of nerve cells and the genetic mutation of KCNQ2/Q3 will alter the function of M channel and may lead to nervous system diseases such as benign familial neonatal convulsions syndrome (BFNCs) (Maljevic S et al., J. Physiol. 2008 586(7):1791-801). KCNQ2/Q3 channel opener can reduce the neuronal excitability, thereby capable of treating diseases associated with neuronal over-excitability such as convulsions, epilepsy and neuropathic pain.
Patent EP554543 discloses a type of KCNQ opener Retigabine (D-23129; N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester). Retigabine has shown a promising anticonvulsant property in vivo and in vitro; is effective in reducing incidence of epilepsy (Bialer et al., Epilesy Research 2002, 52, 31-71). Neuropathic pain experiments based on animal model suggest that KCNQ channel opener can be used for pain disorder treatment (Blackburn-Munro et al., European Journal of Pharmacology 2003, 450, 109-116). In addition, the expression of KCNQ2-5 channel RNA in trigeminal ganglia, dorsal root ganglia and trigeminal caudate nucleus has implied that these channel openers may have an effect on feeling process of migraine (Goldstein et al., Society for Neuroscience Abstracts 2003, 53, 8). There is also report on Retigabine having activity on animal model of anxiety-like behavior (Korsgaard et al., J Pharmacol Exp Ther. 2005; 314(1): 282-92). Researchers also discovered the expression of mRNA of KCNQ2 and KCNQ3 subunits in hippocampus and amygdale which are associated with anxiety behavior and emotional behavior (such as bipolar disorder). It is suggested that KCNQ opener can be used for the treatment of neurological disorders such as anxiety disorder and bipolar disorder. Other researches further discover that KCNQ channel opener can effectively used for treatment of stroke (Jensen B S., CNS Drug Review 2002, 8(4):353-60), and also for treatment of diseases of excessive excitability in which the brain reward system is involved, such as cocaine abuse, nicotine withdrawal symptoms and alcohol withdrawal symptoms (Hansen et al., Eur J. Pharmacol. 2007; 570: 77/88).
In conclusion, KCNQ potassium channel not only involves in regulation of many important physiological functions in the body, but also has significant effect on certain diseases. Accordingly, more research and development of novel compounds for application as KCNQ potassium channel opener can provide more choices for clinical uses.